CN1354656A - Compositions and methods for mucosal delivery - Google Patents

Abstract

The present invention relates to a dosage unit comprising a water-soluble hydrocolloid and a mucosal surface-coat-forming film, such film including an effective dose of active agent. In the dosage unit slidenafil citrate, nicotine, hydromorphone, oxybutynine or estradiol are used as active agents.

Description

Compositions and method that mucosa transmits

The present invention relates to Apparatus and method for the administration of stripping film configuration.

Background of invention

Many pharmaceutical dosage forms are with goods such as tablet, pill, Caplet (cap1et) and the capsular form oral administration of solid shape, these dosage forms in depress the shape that can keep them.Usually these dosage form design Cheng Nengyong sufficient liquid is transmitted medicine through all swallowing or chewing.Some patient particularly Pediatrics Department and elderly patients swallows and chews solid dosage forms and has any problem.Some patient such as child or animal refuse to take medicine, and may attempt to have hidden the solid pill so that later it is spued.In addition, be that active medicine also is difficult to swallow and be retained in throat or the esophagus because liquid is taken with dosage unit even many Pediatrics Departments and elderly patients are reluctant to take solid dosage forms.In addition, the utilization rate during the liquid administration is limited to some patient, and is confined to some disease and/or treatment.Chewable tablet provides some to surpass the advantage of conventional tablet.But they are not suitable for the child of tying up band, and the taste of medicine is unpleasant and be difficult to cover in chewable tablet.Simultaneously, still need water to come the administration chewable tablet.

In addition, standard oral dosage forms such as tablet, pill, Caplet and capsule are to design for short oral cavity retention time.Absorbing the drug from these dosage forms occurs in intestines and stomach (GI), and this separates with dosage form and in gastric juice after the stripping at medicine.For some active medicine, wish that mucosal tissue is finished absorption so that quicken the generation of therapeutic effect in the through port.

Even after many active medicines disperseed under one's belt, they are malabsorption also, because dissolubility is low or dissolution rate is slow in gastric juice.Can be made into quick-dissolving tablet.Usually be placed on these tablets on the tongue and at intraorally rapidly disintegrating.But these dosage units can not be fixed to mucomembranous surface but move around in mouth.Therefore, they can not overcome and suffocate or stop up relevant danger, and suffocating or stopping up is to follow the problem of their swallowing reflexs of limited control to take place.But in case be put in the mouth, the quick stripping in saliva of these tablets provides a kind of liquid preparation that can be swallowed subsequently.Dissolving tablet can be formed by the particulate vector substrate that contains medicine, and wherein particulate vector substrate is protein (United States Patent (USP) 5,807,576, United States Patent (USP) 5,635,210, United States Patent (USP) 5,595,761).Tablet also can be formed (Japan Patent 100535518) by the laminated product with multilamellar and external coating.Tablet also can be prepared by shearing (shearform) substrate that is essentially amorphus sugar, and amorphus sugar is that crystal sugar forms (WO95/07194 through heating and shearing; WO95/35293).Other method that forms dissolving tablet comprises wet granulation (European patent 0,627 218) and dry granulation (European patent 0124027A1) and freeze-drying (European patent 0084705A2).Usually, dissolving tablet is to use complicated multistep autofrettage to form.In addition, the mechanical strength of these tablets is bad, and frangible and not enough maintenance active component (United States Patent (USP) 5,720,974) stores and operating difficulties.

The treatment chemical compound be sometimes provide with the powder that is difficult to swallow or granule and in mouth, produce sensation beastly.In addition, many dissolving tablets contain the granule (＞25 microns) that can stay " sand grains " and taste beastly in mouth.In the adult, powder can cause with granule and is trapped in relevant suffocate and uncomfortable in the denture.Powder and granule are packaged in the sealing pouch of tearing with preceding need.This can have problems to elderly patients and the patient and the child that suffer from the articulations digitorum manus inflammation.Therefore, in this class patient, can produce the leakage problem of inclusions.In addition, these oral formulations must be swallowed by water, and this is to some patient's inconvenience and can cause patient compliance's minimizing.

The alternative solid dosage forms of liquid, syrup or suspension and be ideal to problematic Pediatrics Department of swallow tablet and elderly patients.But these dosage forms usually are difficult to accurately measure and the administration difficulty.Liquid preparation goes bad rapidly when being exposed among heat and the atmosphere, so shelf life is shorter.In addition, liquid preparation needs larger volume and reservoir volume huge.

Except solid and liquid dosage form, people have developed instant cheek/oral delivery system.These systems are generally freeze-dried preparation, and it compares preparation expensive (United States Patent (USP) 5,648,093) more with tablet.In addition, frangible during the freeze-dried preparation operation, must remain under the drying condition in case disintegrate.Can reduce the unstability (United States Patent (USP) 4,946,684) of freeze-dried preparation by interpolation mannitol to a certain extent.WO9820862 has reported a kind of thin film that forms according to a certain method, and this method does not utilize lyophilization and the problem that can avoid describing in the art such as thin film rigidity, softening delaying and orally-dissolvable property bad (United States Patent (USP) 4,876,092; European patent 0200508; EPO 0381194; CA-PS 1-26331; DE2449865.5; DE3630603; European patent 0452446 and European patent 0219762).But the thin film of describing in WO9820862 depends on and uses two kinds of different non-ionic surface active agents to reach quick humidification at least.

Wish that dosage unit provides a kind of and do not invade, efficient and economic mode is delivered to target position with active medicine.Target position be the place of blood plasma produced and medicine to the relevant other problem of transfer rate (measuring) at this position by bioavailability.With regard to the active medicine of many types, wish that therapeutic effect can begin fast.The time started of traditional oral formulations (as tablet) is limited by the absorption rate in the gastrointestinal tract.The preparation of having developed begins in being applied to mouth the time faster than traditional oral dose because they with mucosa in the mouth as target position.These preparations comprise contain 75%-90% can be at the dosage unit (United States Patent (USP) 5,004,601 and 5,135,752) of the Polyethylene Glycol of mouth endosome relaxing the bowels with purgatives of warm nature fusing.Other preparation comprises sublingual administration or liquid type, lozenge or tablet (United States Patent (USP) 5,770,606, people such as people such as Streisand and Zhang, people such as Christie, people such as Sasaki) by sweet substrate administration on the patch.Though above-mentioned description has been considered bang path, they do not have to consider because the bioavailability problem that the bad or low dissolution rate of dissolubility causes.

Having considered above-mentioned circumscribed transmission equipment means, existing transmission system has been carried out gratifying improvement.

Summary of the invention

A kind of novel dosage unit and its method of manufacture and use thereof are provided.In one embodiment, dosage unit comprises that a kind of water solublity hydrocolloid, mucomembranous surface form the film of coating, and this film comprises the active medicine of effective dose.

In one embodiment of the invention, hydrocolloid comprises that a kind of being selected from comprises polymer natural, half-natural and synthetic biopolymer (is example with polysaccharide and polypeptide).Except hydrocolloid, this film also comprises one or more emulsifying agents, plasticizer, flavor improving agent, water solublity inert filler, antiseptic, buffer agent, coloring agent, penetration enhancer and stabilizing agent in addition.This film also comprises a kind of active medicine that comprises therapeutic agent, nutritional supplement and health-care agent that is selected from addition.Embodiment of the present invention has adopted sildenafil citrate, nicotine, hydromorphone, oxibutynin or the estradiol of capacity to be used as active medicine in dosage unit.This active medicine can be encapsulated in second kind of polymer that stripping property is different from hydrocolloid.The active medicine that can comprise more than one in the film.In one embodiment of the invention, the concentration of emulsifying agent can be 0.1-10% (weight).The water inert filler can comprise the concentration range of 0.5-50%, and antiseptic can comprise the concentration range of 0.01-10%.A kind of mucosal adhesive promoter (as starch graft copolymer) can be included among the dosage unit.

In embodiment of the present invention, dosage unit also comprises following arbitrary feature in addition: dry film thickness range is 1-20mil, more especially less than 10mil, the aggressive tack value is less than 3.5 grams, more especially less than 2 grams, wet viscosity value is greater than 35 grams, and hot strength is greater than 1500psi, modulus ranges is 35,000-300,000psi, anti tear extensibility scope is 0.001 N-1 N, the disintegration time scope is 1-300 second, and the dissolution time scope is that 10-600 second and percentage elongation are less than 20%.

The method for preparing dosage unit is provided in embodiment of the present invention, these methods comprise in one embodiment dissolves hydrocolloid so that form a kind of preparation of basic homogenizing in a certain solvent, add active medicine and at least a reagent that comprises emulsifying agent, plasticizer, flavor improving agent, water solublity inert filler, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent that is selected in the hydrocolloid preparation a kind of mixture that is coated with of formation, and form the packing of the film of coating as dosage unit with a kind of mucomembranous surface that forms from this mixture.This method also comprises in addition mixture is applied to this step of counterdie.In another embodiment, reagent comprises hydrocolloid, active medicine and at least a reagent that comprises emulsifying agent, plasticizer, taste modifying agent, water solublity inert filler, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent that is selected from, can be by the combination in the container of being furnished with thermal source and mechanical mixing equipment of any order, the merging composition is mixed during composition adds container to and afterwards, with the softening most of mixture of efficient heat.This mixture forms film to do squeezing and pressing method then.

In one embodiment of the invention, a kind of method that active medicine is given the subject is provided, it comprises the film that obtains a kind of water solublity hydrocolloid, mucomembranous surface formation coating, this film comprises the active medicine of effective dose, and this film is placed on the interior mucomembranous surface of subject through being coated with on the film that forms so that discharge active medicine.

In another embodiment of the present invention, provide a kind of dosage unit that is included in the sildenafil citrate of water solublity hydrocolloid in the mucomembranous surface contact membranes and effective dose.Particularly, the sildenafil citrate of effective dose and xylitol formation solid dispersion is used for the treatment of erection disturbance.This sildenafil/ xylitol dispersion can with at least a reagent mix that comprises emulsifying agent, plasticizer, flavor improving agent, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent that is selected from.The solid dispersion of Sildenafil and xylitol is by 9 parts of sildenafil this ratio of 1 part of xylitol to be produced.According to the embodiment of the present invention of the method for making that has related to the dosage unit that is applicable to erection disturbance and dosage unit, the water solublity of the sildenafil in solid dispersion is at least 20 mg/ml, more especially about 50 mg/ml.Particularly, can be at this film of oral mucosa surface in 10-600 stripping fully in second.

The accompanying drawing summary

Fig. 1 has illustrated that dosage unit of the present invention is at intraoral possibility application site.(1) is upper lip; (2) be gingiva; (3) be hard palate; (4) be buccal; (5) be tongue; (6) be the Sublingual; (7) be lower lip.

Fig. 2 has illustrated a kind of production method of dosage unit.(8) be to mix and degassing tank; (9) be the coating pan of being furnished with thickness controller; (10) be moving band behind the polyester; (11) be the baker of being furnished with the Ventilation Control instrument; (12) be endoral membrane; (13) be cross cutting; (14) be a mouthful interior dosage unit.

Fig. 3 has illustrated the example that is used for mouthful packing of interior transmission system and dispensing equipment.(15) be the single capsule of heat-sealing; (16) be many units blister web; (17) be many identity component packings; 17 (a) container snap-fastener (snap) and 17 (b) lid; (18) be many units roller distributor cylinder; (19) be the porous membrane band; (20) be the single dose film.

Fig. 4 has proved the disintegrate of mouthful interior transmission system and the function that dissolution time is thickness.----be that disintegration time and--zero--are dissolution times.

Fig. 5 has illustrated----nicotine,----oxibutynin,--●--the release profiles of hydromorphone and--zero--estradiol.

Fig. 6 has illustrated behind the administration stripping film sildenafil preparation and administration contains the pharmacokinetics in six subjects after the commercial tablets of sildenafil of same dose.Sildenafil film--zero--Viagra----.

Detailed Description Of The Invention

The transmission of solid-state active medicine per os can have problems to the patient who suffocates because of dosage unit.This result to small part be since mouthful in the flowability of dosage unit cause.We have developed a kind of new dosage unit, and it can not flow in mouth, because it contacts with wet mucomembranous surface.This film becomes the coating that can adhere to mucomembranous surface, then disintegrate and stripping in the time range of dosage design control.In one embodiment of the invention, dosage unit is a kind of flexibility, sticking, a drying packaging film form easily.In case remove and be placed on mucomembranous surface from packing, the film of mucomembranous surface formation coating is basic hydration formation coating on the wet surface of mucosa immediately, and disintegrate and stripping discharge active medicine from film then.

The active medicine that dosage unit discharged in a period of time is to be determined by many different factors.These factors comprise the size of film, the concentration of active medicine, and how dispersive by thin film medicine is at the dissolubility and the medicine of mucomembranous surface.Film thickness is a factor of decision dissolution rate.The thick film thin film stripping more similar than others is slower.The volume of thick film is ideal to the volume of holding of the active medicine that needs high dose.Though the surface area of film is adjustable to up to 5 square centimeters, in order to obtain effective active medicine dosage, it also may be ideal increasing thickness.It is exactly in order to increase the bioavailability that the dissolubility of medicine when thin film discharges improves active medicine thus that active medicine and water solublity inert filler form solid dispersion.The example here has with water solublity inert filler (as xylitol, having found that here it can improve the bioavailability of this medicine) and joins the sildenafil in the film together.The solubilizing agent that is well known in the art can be included in the film.Active medicine can be controlled by the dissolution rate of film from the degree of absorption of dosage unit at mucomembranous surface.The stripping film will discharge active medicine, and this will cause successively that active medicine is swallowed and is absorbed in gastrointestinal tract.On the contrary, medicine will cause the increase that mucomembranous surface absorbs in the slow release of mucomembranous surface.The control active medicine is medicine dispersive mode in film in another parameter that mucomembranous surface discharges.For example, medicine can be disperseed as the microcapsule in colloidal solid or the film, maybe can mix as a kind of reagent during the curtain coating (casting) by film.

Dosage unit of the present invention can be used as the carrier that transmits various active medicines.For example, active medicine can be micromolecule, protein, comprise nucleic acid or other biology or the synthetic molecules of antisense (antisense) molecule.

In this description and following claims, may be used on the term " mucomembranous surface formation coating " of film (unless otherwise indicated), refer to that film is applied to mucomembranous surface by contact, after this remove without manual recovery or from the contact site, disintegrate subsequently and stripping are so that discharge active medicine.Should be noted that for description of the present invention and claims " mucomembranous surface " refers to any wet surface of human body.This comprises the surface that Fig. 1 middle finger is appeared.Comprise also that in addition lymph fluid soaks the wound surface of tissue surface.

Embodiment of the present invention comprises method, compositions and the using method of medicine localized delivery or systemic delivery being given the instant film that subject's mucomembranous surface uses.Hereinafter, by way of example specific reference is done in the oral cavity.But, do not plan scope of the present invention is confined to the oral cavity.Dosage unit of the present invention may be used on being considered to be applicable to any mucomembranous surface (comprising vagina, rectum and ocular surface) of medicine systemic delivery or localized delivery.For oral delivery, film can be applicable to tongue, Sublingual, cheek, gingiva and palate surface (Fig. 1).

For vagina transmission such as the contraceptive that comprises nonoxynolum or comprise anti-infective or the aromatic or the health-care agent of antifungal, antibacterial and antiviral agent, film should cannot not be sticking when from the packing taking-up, must have mucosa-adherent in the time of still in being applied to vagina.Though used the film that contains active medicine that uses in vagina, they have looked many and obvious defects have most particularly lacked adhesiveness at mucomembranous surface.This makes that these film administrations are unrealistic.(United States Patent (USP) 5,380,529; 5,595,980 and 5,529,782).

Embodiment of the present invention provides the improvement dosage form and the easily administration of internist, father and mother, patient and kinsfolk that are used for transmitting active medicine that is fit to all age group.These dosage form preparation economy also have longer shelf life.Before the administration their easy operatings and sticking be exactly disintegrate before use, pack easily and be suitable for shelf life, store and distribute simple and easy.This dosage form can be given the subject by film being placed on skin and mucocutaneous administration, and at this moment film becomes the mucosal adhesive coating, and its characteristic no longer exists and is dispersed in the solution subsequently with form independently for it.

Embodiment of the present invention provides a kind of and is used in wet mucomembranous surface (for example in the oral cavity) stripping and discharges their active medicine of content or the transmission system of other medicines fully.Need not of drug release chewed or fed water.With reference to the oral cavity, embodiment of the present invention provides and has residued in the active medicine that is used for the treatment of in the oral cavity or improves a mouthful interior environment (for example periodontal disease therapeutic or breathing-abnormal smells from the patient control) by specific.In addition, the improvement that the present invention provides in addition comprises: improvement organoleptic attribute (abnormal smells from the patient and taste), and plan is placed on the structure and the sensation of intraoral dosage form; Dosage form " is softened " in mouth and stay pleasant level and smooth back sense after stripping, active medicine is trapped in the time of staying that can prolong active medicine in the mouth for a long time after the Expidet stripping, this active medicine is removed by the saliva that produces and swallowing from mouth subsequently.The preferred plan of application-specific according to the present invention, disintegration time and dissolution time can be controlled in the prescribed limit by adjusting preparation and thickness.Sometimes, the release of wishing active medicine occurs in after the stripping of film.With regard to these application, active medicine can be encapsulated in the material that stripping property is different from hydrocolloid.Also can utilize the encapsulation of active medicine to reach the taste of the medicine that covers bitter in the mouth.The different activities medicine that sometimes, can comprise two or more in the film.Often an example of the various active drug administration that adopts is the coldrex that usually contains several active medicines.

Here and " coating fluid " that in claims, define refer to hydrocolloid, active medicine and other additive a kind of viscosity and the uniform homogeneous blend in solvent.Coating fluid is handled by the inventive method and is formed film.

Here and " subject " that in claims, define refer to the human or animal.

Here and " thickness " that in claims, defines measure with mil (1mil=mil), it is measured when film is placed between two micrograms.

Here and " penetration enhancer " that in claims, define refer to promote the natural or synthetic molecules that active medicine absorbs by mucomembranous surface.

Here and " enzyme inhibitor " that in claims, define refer to suppress the natural or synthetic molecules of the enzymes metabolism of active medicine in saliva or mucosal tissue.

Here and " moisture content " that in claims, define refer to the residual moisture content of the per unit dosage measured according to Karl Fisher method and represent with the percentage rate of film dry weight.

Here and " hydration rate " that in claims, define refer to the absorption speed in 24 hours under 25 ℃ and 75% relative humidity.

Here Ding Yi " swollen percentage " refers to the percentage rate that initial volume increased before stripping.In embodiment of the present invention, swollen percentage in 60 seconds less than 10%.

Flavor improving agent comprises correctives, sweeting agent and taste screening agent, example has the water solubility extract of quintessence oil or menthol, wintergreen oil, Oleum menthae, sweet Herba Menthae, Mentha viridis L, vanillin, Fructus Pruni pseudocerasi, chocolate, Cortex Cinnamomi, Flos Caryophylli, Fructus Citri Limoniae, orange, raspberry, Flos Rosae Rugosae, spice, common violet, herbaceous plant, fruit, Fructus Fragariae Ananssae, Fructus Vitis viniferae, Fructus Ananadis comosi, peach, kiwi, Fructus Caricae, Fructus Mangifera Indicae, Cortex cocois radicis, Fructus Mali pumilae, coffee, Fructus Pruni salicinae, Citrullus vulgaris, nut, durean, green tea, grapefruit, Fructus Musae, Adeps Bovis seu Bubali, Chamomile, sugar, glucose, lactose, mannitol, sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, glucide, saccharin sodium, sodium cyclamate and Mel.

Emulsifying agent comprises solubilizing agent and wetting agent, and example has polyvinyl alcohol, sorbitan ester, cyclodextrin, benzyl benzoate, glyceryl stearate, polyoxyethylene alkyl ether, Myrj 45, poloxamer, castor oil derivatives, hydrogenated vegetable oil, bile salts, polysorbate and ethanol.

Plasticizer comprises glycerol, sorbitol, propylene glycol, Polyethylene Glycol, triacetin, triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and other citrate.

Active medicine (being used for the human or animal) comprises therapeutic agent, nutritional supplement and health-care agent.The example of therapeutic agent is an analgesic, the alpha-adrenergic receptor blocker, the Kang Aercihaimoshi medicine, the anti-sphagitis medicine, antianxiety drugs, antiarrhythmics (antiarrythmics), antiarthritic, antibiotics, anticoagulation/thrombolytic agent, convulsion/anti-Parkinson medicine, antidepressants, antidiabetic, diarrhea, antuepileptic, antifungal, the gout agent, anti-heart worm medicine, antihistaminic, antihypertensive, anti-inflammatory agent, anti-infective, antimigraine, anti-nasuant/ antiemetic, antineoplastic agent/anticarcinogen, pruritus, control chlorpromazine, antipyretic, anti-spasmodics, antiviral agents, bronchodilator/control asthma medicine, calcium antagonists, cardiac tonic, cardiac tonic, central nervous system's medicine, contraceptive, coronary artery diastole agent, cough/coldrex.Nutritional supplement comprises vitamin and mineral, diuretic, fertility drug, animal control flea agent (ivermectin), the hydrogen acceptor antagonistic, the herbaceous plant medicine, hormone, blood sugar lowering, hypolipidemic, muscle diastole agent, the ovulation exciting agent, the peptide medicine, peptide drug, protein is (as insulin, calcitonin, LHRH etc.), tranquilizer and hypnotic, the sexual dysfunction medicine, somnifacient, Ling " for giving up smoking, steroid and steroid, tranquilizer, cathartic, ophthalmic preparation, nutritional supplement, breathe fresh dose, the breathing deoderization agent, Mouthkote, the antigingivitis agent, the hole agent of anti-dental caries, anti-plaque agent, diagnosis developer and local anesthetic.The medicine, antiseptic, corticosteroid medicine, non-steroidal anti-inflammatory agent, antiviral agents and the vaccine that also comprise the osteoporotic medicine of treatment, hormone replacement medicine, treatment periodontal disease.

The water solublity inert filler comprises mannitol, xylitol, sucrose, lactose, maltodextrin, glucosan, dextrin, modified starch, glucose, sorbitol and dextrates.The water solublity inert filler is used as the inert carrier that can form the highly-water-soluble dispersion with medicine in embodiment of the present invention.

Buffer agent comprises acidulant and basifier, and example has citric acid, fumaric acid, lactic acid, tartaric acid, malic acid and sodium citrate, sodium bicarbonate and sodium carbonate, sodium phosphate or potassium and magnesium oxide.

Coloring agent comprises FD﹠amp; C coloring agent, natural colorant and natural concentrated juice, pigment (as titanium oxide, silicon dioxide and zinc oxide).

Here with claims in the stabilizing agent that uses comprise antioxidant, chelating agen and enzyme inhibitor, example has ascorbic acid, vitamin E, butylatedhydroxyanisole (BHA), Yoshinox BHT (BHT), propyl gallate, dilauryl thiodipropionate, sulfuration dipropionic acid, guaiac gum, citric acid, ethylenediaminetetraacetic acid and salt and glutathion.

Here antiseptic comprises antibacterial and non-organic compound, and example has sodium benzoate, metagin and derivant, sorbic acid and salt thereof, propanoic acid and salt thereof, sulfur dioxide and sulphite, acetic acid and acetate, nitrite and nitrate.

The mechanical performance of film is by hot strength modulus, percentage elongation (ASTM D882, the standard testing method that is used for the thin plastic sheet tensile properties) and anti tear ductility (ASTM D1938 adopts the ductile standard testing method of anti tear of the plastic foil and the thin slice of single method of Tearing) determine.Here mechanical performance is to use Annual Book of ASTM, ANSI, and the standard agreement of describing in the New York 1995 is measured.

" hot strength " is to need load to cause the membrane property that the film load deformation reduces (psi).

" % elongation " is to measure when surpassing elastic limit when using enough power to break film.

" releasing research " is the percentage rate that active medicine discharges from film, and it is the function of time under specified temp and pH condition in suitable stripping container and medium.

" aggressive tack " is the dry film viscosity quantitative values (gram) (model TA.XT2i, the rustless steel cylinder detector that the employing diameter is 6 millimeters) according to the Texture Analyzers of Texture Technologies company.Viscosity after adding 10 ml waters on the identical surface area is defined as simulating thin film and the adherent wet viscosity of wet mucomembranous surface (gram) on the contact surface.In embodiment of the present invention, aggressive tack is the 0.2-3.5 gram, preferred 0.4-2.0 gram, and wet viscosity is the 35-150 gram, preferred 40-100 gram.

Here with in claims tear on film or the sheet under " the anti tear extensibility " that define specific rate of extension of referring in ASTM D1938, define and extend required mean force (cattle) and be illustrated at duration of load application figure.In a preferred embodiment of the invention, the anti tear extensibility is 0.001 N-1 N, preferred 0.01 N-1 N.

Here with claims in " disintegration time " that define broken time (second) when referring to that the film introducing contacts with water or saliva.In embodiment of the present invention, disintegration time is 1-300 second.

Here with claims in " dissolution time " that define refer to be no less than time (second or minute) of test membrane stripping in aqueous medium or saliva of 80%.In embodiment of the present invention, dissolution time is 10-600 second.

" modulus " can measure the rigidity of film.

The characteristic that determines mucomembranous surface to form the compositions of coating is played the viscosity that factor is a hydrocolloid of remarkable effect.The viscosity of hydrocolloid depends on other additives that occur in molecular size, derivant, hydrophobicity and hydrophilic and the preparation.The film that contrast is formed by hydrocolloid, hydroxy methocel, this film has the different viscosities value, shown in table 9a and 9b.

In embodiment of the present invention, it is the 5-99% of film dry weight that a kind of concentration range is provided, more especially greater than 10% hydrocolloid.These films have the aggressive tack and the wet viscous characteristics of the easy degree that can improve operation and use.The low aggressive tack of film provides certain actual captivation, and film easy to operate had been both non-friable also not to be clamminess and to be easy to and remove and place mucomembranous surface from packing.The wet viscosity of the film advantage that is clamminess to wet film provided is exactly in order to be placed on the mucosa when film, and it remains adhered to this position up to its stripping.On the contrary, if wet viscosity is too low, thin film moves in mouth, may be swallowed and may cause before the stripping and suffocate.In addition, the low-water-content of film and the low aggressive tack motility that prolonged the shelf life of thin film and improved dosage form.These characteristics make thin film be convenient to preparation, packing, operation and application.

In embodiment of the present invention, select gelling temp to be higher than 70 ℃ water-soluble polymer (2% polymer solution).The hydration rate of hydrocolloid with these features is very fast, and promptly the suction percentage rate of polymer is 5-20% under 75% humidity and room temperature.Select hydration rate can avoid demand thus according to the required wettability of film to surfactant.The wet viscosity of hydrated film is the 35-150 gram, more especially the 40-100 gram.Swollen percentage can be less than 10% in 60 seconds.With the film curtain coating is exactly in order to obtain the thickness of 1-20mil.The moisture content of film is 0.5-10%, preferred 1-5%.In embodiment of the present invention, it is that the mixture of the different identical hydrocolloid of molecular weight and/or replacement degree forms that film can use two or more.The film dissolution time is (see figure 4) in 10-600 scope second, and the film disintegration time can be 1-300 second.Active medicine in the film can be encapsulated in the polymer of hydrocolloid that chemistry or physical characteristic and stripping feature be different from film.Table 1,3,6,7 provide according to what the present invention formed and have had a example at the thin film of above-mentioned scope internal characteristic.

Easy to operate is that aggressive tack by film characterizes, and flexibility is hot strength, modulus, % elongation and the tear resistance reflection by thin film.For example, aggressive tack is the 0.2-3.5 gram, more especially the 0.4-2.0 gram.For thickness is the film of 2mil, and hot strength is 1500-10,000psi, and 2000-8000 more especially, more especially greater than 2000psi, modulus is 35,000-300,000, % extends less than 20%, more especially 1-10%.

In embodiment of the present invention, hydrocolloid is the non-gel of water solublity (at room temperature) natural polysaccharide or derivant, comprise pectin and derivant, Arabic guar gum, Tragacanth, gellansodium salt, propanediol alginate, starch (amylose, amylopectin), modified starch, hetastarch, pullulan, carboxymethyl starch, Ficus elastica, Flos abelmoschi manihot glue, karaya, glucosan, dextrin, maltodextrin, Rhizoma amorphophalli, acemannan from aleo, locust bean gum, thorn pod tannic extract, smoke tree glue, the sub-glue of Semen Trigonellae, scleroglucan, arabic gum, psyllium seed glue, tamarind gum, oat gum, smoke tree glue, carrageenin, scleroglucan, succinoglucan, the larch arabinogalactan, Semen Lini natural gum, chondroitin sulfate, hyaluronic acid, curdlan, chitosan, remove acetyl Rhizoma amorphophalli and rhizobium glue.

In embodiment of the present invention, hydrocolloid is non-gel polypeptide of water solublity or protein, and example has gelatin, albumin, cow's milk protein, soybean protein and lactalbumin.Hydrocolloid also is selected from the synthetic water colloid in addition, with following any is example: polymine, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, polyacrylic acid, low molecular weight polyacrylamide and their sodium salt (acrylate copolymer), polyvinylpyrrolidone, Polyethylene Glycol, poly(ethylene oxide), polyvinyl alcohol, the block copolymer of epoxy ethane-epoxy propane, tetronics and other block copolymer, carboxy vinyl polymer and colloidal silica.The preferred embodiment of the invention adopts has about 19-30% methoxyl content and 7-12% hydroxypropyl content and about 50,000-250, the hydroxypropyl emthylcellulose of 000 Dalton molecular weight (table 9).

Except hydrocolloid and active medicine, thin film can contain following arbitrary composition or all the components: emulsifying agent, solubilizing agent, wetting agent, flavor improving agent, plasticizer, active medicine, water solublity inert filler, antiseptic, buffer agent, coloring agent and stabilizing agent.In preferred embodiments, the dry weight concentrations percentage rate of the single component at least (each of following kind of apoplexy due to endogenous wind) in the introducing film is as follows: emulsifying agent (0.1%-10%), plasticizer (0.5-20%), active medicine (0.01-75%), flavor improving agent (0.1-10%), coloring agent (0.01-5%), water solublity inert filler (0.5-50%), antiseptic (0.01-10%), buffer agent (0.1-10%) and stabilizing agent (0.01-5%).

The method for preparing dosage unit of the present invention comprise as shown in Figure 2 the solvent cast method or embodiment 11 in other extrusion molding of enumerating.Extrusion molding comprises that the heat that uses mechanical force and appropriateness mixes component and forms film.Obviously, said method does not need the lyophilization step.It is overheated or supercool that said method does not need at production period yet.

In embodiment of the present invention, the solvent cast method comprises complete stripping or the natural or synthetic water colloid that is scattered in the water or in the aqueous alcohol solutions mix is formed homogeneous preparation.Except active medicine and hydrocolloid, can or be dissolved in the hydrocolloid solution the above arbitrary composition interpolation enumerated and homodisperse.Medicine and correctives can add before or after film forms.With this solid content is that 5-50% and viscosity are uniform homogeneous blend (coating fluid) degassing (8) of 500-15000cps and the wet-film thickness (9) of pressing 5-50mil, more preferably the wet-film thickness of 5-20mil is coated on the not silication side of polyester film (10), ventilate and 40-100 ℃ temperature under drying in case the medicine unstability that contains in the preparation (11).Fig. 2 has illustrated the production method that forms dosage unit.The dry film of Xing Chenging is a kind of have light, independence, self-support, not sticking flexible membrane (12) by this method.Then dry film is cut into suitable shape (13) and surface area and is used for active medicine transmission at preferred site.For example, casting films can use rotating die head to be die-cut to different shape and size.For example film can be cut into a certain size that contains single dose.For example, dosage unit comprises that surface area is that 5 square centimeters, contained active medicine dosage are the film of 20-250 milligram (14).The big I of film changes according to required dosage.Contained dosage is selected according to active medicine in every square centimeter.Film is packaged in single pouch-packaged, many units blister web or the many units allotter (Fig. 3) then.

Opposite with said method, dried extrusion molding does not need hydrocolloid is put in a certain solvent.But the dosage unit composition is mixed together with dry state and heats.Make the admixture that heated form the film of selected thickness by extrusion die then.Then film is cut and packing.

Dried extrusion molding has many advantages.At first, it is a kind of method of economy.Secondly, because there is not baker, film extrusion ratio solvent application is faster.The 3rd, dried extrude to have saved remove this step of residual solvent.Some solvents are present in the solvent application method usually and influence the safety or the stability of film.What need at film is the place of organic solvent rather than water, removes to desolvate from film and need pass through environmental legislation.Extrusion molding has saved and has reclaimed any needs of solvent side by side except the residual solvent in the film.

Can prepare dosage unit for use by selecting a certain film, this film can transmit effective dose and by film being placed on mucomembranous surface (as oral mucosa) the film administration be given patient (Fig. 1), wherein film stripping in body fluid (as saliva) (0.5-10 minute) and swallow with liquid state.Fig. 4 has illustrated the disintegrate and the dissolution rate of the film of different-thickness with diagram method.Fig. 5 has illustrated that four kinds of medicines are from the release profiles according to the film of embodiment 5-8.The part of the dosage that absorbs by mucosal tissue can be promoted by use penetration enhancer in film.

In the mucosa part and the active medicine that provides with traditional oral tablet or capsule formulation of total bioavailability of the medicine that absorbs of gastrointestinal tract system whole body and Isodose compare and improved.The bioavailability of for example understanding the Sildenafil film in Fig. 6 and table 11 is better than Viagra.The oral retention of film, mouthfeel, aroma and flavor can be improved based on preparation film and used hydrocolloid and other excipient of medicine.

The present invention will be described and the embodiment that provides below is not provided.According to embodiment 1-8, dissolving forms a kind of uniform viscosity liquid to hydrophilic colloid in water through mixing.Then other composition (as Herba Menthae, aspartame, propylene glycol, benzoic acid and citric acid) is added in the viscosity liquid up to their homodisperse successively or is dissolved in the hydrocolloid through mixing.In vacuum chamber, final mixture is outgased up to removing the bubble of catching.Measure viscosity, pH value and proportion.By 10mil wet thick preparation is coated on the non-silication side of polyester film then and in 50 ℃ hot air circulate stove dry 9 minutes.Dry back obtains a kind of have light, substantially transparent, independence, self-support, not sticking flexible membrane.Dry film is cut into difformity is used to measure aggressive tack, wet viscosity, hot strength modulus, percentage elongation, tear resistance, residual moisture content, disintegrate and stripping.This dosage form is the dosage form of 25-250 milligram difformity, size and thickness.

Embodiment 9 has illustrated how the characteristic of dosage unit when using different hydroxy methocel polymer changes.Embodiment 10 has illustrated how to use promoter (being example with starch graft copolymer) brings up to mucosal adhesive up at least 84%.In vivo dosage unit be studies show that it can be well obtained to improve (embodiment 13) by patient's tolerance (embodiment 12) and bioavailability.

EXAMPLE Example 1-3: instant film, composition and correlation properties

Film prepares as follows: press data that table 1 is given prepare a kind of homogenizing in coating fluid constituents mixt.Data are that the weight percent by coating fluid provides.Mixture outgased in vacuum chamber and be coated on the not silication side of polyester film, dry a kind of self-support, the not sticking flexible membrane of forming in the hot air circulate baker.Then this film is cut into dosage unit in order to packing.Table 1: the preparation that uses the instant film of several different hydrocolloids

Form: coating fluid %	Embodiment 1	Embodiment 2	Embodiment 3
				Pullalan (P-20) % (weight)		17.5
Methocel E5% (weight)	21.06
				POLYOX WSR N-10% (weight)			?1.8
PVA (Vinol 125) % (weight)		1.5
				Cellulose gum % (weight)			?8.1
Propylene glycol % (weight)	1.0		?2.5
				Aspartame % (weight)	0.8	?0.475	?0.46
Herba Menthae % (weight)	1.0	?1.0	?0.6
				Citric acid % (weight)	0.7	?0.8
Cremphor EL40% (weight)	1.0	?1.0
				Benzoic acid % (weight)	0.013	?0.1	?0.01
The blue #1% (weight) of FD﹠C	In right amount
				The yellow #5% (weight) of FD﹠C	In right amount
Ethanol % (weight)		10.6
				Water % (weight)	74.42	?67.025	?85.6

Table 2: the characteristic of the film that forms by the coating fluid of table 1

The dry film characteristic	Embodiment 1	Embodiment 2	Embodiment 3
				Thickness (mil)	2.1	?2.5	?2.6
Moisture content %	1.7	?8.5	?8.0
				Aggressive tack (gram)	0.67	?0.55	?0.60
Wet viscosity (gram)	60.16	?86.64	?72.27
				Hot strength (psi)	5242	?2381	?2036
% extends (second)	2.9	?4	?2.9
				Modulus (psi)	266834	?272502	?44566
Tear resistance (cattle)	0.02	?0.16	?0.01
				Disintegrate (second)	12	?20	?12
Dissolution time (second)	41	?60	?39

Table 3: according to the dry weight percentage rate of the component of the embodiment 1 of table 1 and table 2

Composition	Percentage rate (w/w)
		Methocel?E5	?82.35
Propylene glycol	?3.91
		Aspartame	?3.13
Citric acid	?2.74
		Oleum menthae	?3.91
The PEG-40 castor oil hydrogenated	?3.91
		Benzoic acid	?0.5
The blue #1 of FD﹠C	In right amount
		The yellow #5 of FD﹠C	In right amount

Table 4: according to the meansigma methods of the parameter of the embodiment in the table 11

Characteristic	Value	± standard deviation (n)
			Weight (gram/dosage film)	0.028	?0.001(4)
Thickness (mil)	2.1	?0.12(3)
			pH	?3.07	(1)
Density (gram per centimeter 3)	1.0485	?0.009(3)
			The % moisture content	1.7	?0.24(2)
Aggressive tack (gram)	0.674	?0.110(6)
			Wet viscosity (gram)	60.169	?11.680(6)
Hot strength (psi)	5242	?379(5)
			The % elongation	2.9	?0.4(5)
Modulus (psi)	266834	?7910(5)
			Tear resistance (cattle)	0.02	?0.00(4)
Disintegration time (second)	12	?1(3)
			Dissolution time (second)	41	?5(3)

Embodiment 4-8: the instant endoral membrane of hydroxypropyl methylcellulose based that contains therapeutic agent

Prepare film according to embodiment 1-3.Before film forms, therapeutic agent is added in the uniform homogeneous blend (coating fluid).Table 5

Form (coating fluid)	Embodiment 4	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
						Nicotine		1.4
Hydromorphone			2.92
						Oxibutynin				3.71
Estradiol					1.49
						Herba Menthae	1.0	?1.0	?1.0	?1.0	?1.0
?Methocel?E5(HPMC)	21.06	?21.06	?21.06	?21.06	?21.06
						Propylene glycol	1.0	?1.0	?1.01	?1.0	?1.0
Aspartame	0.8	?0.8	?0.8	?0.8	?0.8
						Citric acid	0?7	?0.7	?0.7	?0.7	?0.7
?Cremphor?EL?40	1.0	?1.0	?1.0	?1.0	?1.0
						Benzoic acid	0.013	?0.013	?0.013	?0.013	?0.013
The blue #1 of FD﹠C	In right amount
						The yellow #5 of FD﹠C	In right amount
Water	74.43	?73.03	?71.51	?70.72	?72.94

Table 6: the characteristic of the film that forms according to the preparation in the table 5

Characteristic	Embodiment 4	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
						Thickness (mil)	3.0	?2.9	?2.9	?3.2	?2.7
Density (gram per centimeter 3)	1.18	?1.19	?1.13	?1.20	?1.16
						The % moisture content	1?8	?2.93	?2.42	?2.32	?2.31
Aggressive tack (gram)	0.67	?0.608	?0.619	?1.215	?0.671
						Wet viscosity (gram)	49.08	?54.81	?84.34	?88.85	?39.91
Hot strength (psi)	4393	?3373	?4138	?3549	?3688
						% extends (second)	8.3	?8.3	?7.6	?8.1	?7.5
Modulus (psi)	45969	?48168	?42110	?41745	?53334
						Tear resistance (cattle)	0.03	?0.02	?0.01	?0.03	?0.01
Disintegrate (second)	43.0	?34.3	?27.3	?36.0	?55.7
						Dissolution time (second)	73.7	?64.3	?58.0	?65.7	?111.3

The composition (% wet basis) of table 7:Sildenafil film

Form	Percentage rate
		Sildenafil?citrate	?28.93
Xylitol	?3.21
		?Methocel?E15	?4.59
Propylene glycol	?3.67
		Aspartame	?0.46
Benzoic acid	?0.0045
		Oleum menthae	?0.46
Sodium ethylene diamine tetracetate	?0.0045
		?Polyoxamer?L-44	?2.3
Water	?55
		?Polypro?5000	?0.92

Table 8: the characteristic of the film that forms according to the preparation in the table 7

Characteristic	Embodiment 9
		Thickness	??3.2±0.1
Density (gram per centimeter 3)	??1.230
		Aggressive tack (gram)	??1.21±0.19
Wet viscosity (gram)	??23.79±3.45
		Hot strength (psi)	??421±49
% extends (second)	??4.0±0.7
		Modulus (psi)	??31822±6137
Tear resistance (cattle)	??0.04±00
		Disintegrate (second)	??8.3±1.5
Stripping (second)	??23.7±1.5

Embodiment 9: use the contrast of characteristic of the dosage unit of different hydroxypropyl methyl cellulose polymers

Characteristic according to dosage unit of the present invention can be improved by changing individual components.For example, the stripping of thin film can have the more high-molecular weight hydroxypropyl emthylcellulose shown in the following table 9 by use and prolonged.Table 9a: the characteristic of selected commercially available hydroxypropyl methyl cellulose polymers

Characteristic	Methocel type (Dow Pharmaceuticals)
									E3	?E5	?K3	?E15	?A15	?E50	?F50
The % methoxyl group	29	?29	?22	?29	?30	?29	?28
								The % hydroxypropyl	8.5	?8.5	?8.1	?8.5	?0	?8.5	?5.0
Viscosity 2% (cps)	2-4	?4-6	?2-4	?12-18	?12-18	?40-60	?40-60

^*Each value is the meansigma methods of standard ± deviation, and n=6 shows 9b: the characteristic of using the film of different hydroxypropyl methyl cellulose polymers preparations according to embodiment 1

Characteristic	E3	?E5	?K3	?E15	?A15	?E50	?F50
								Aggressive tack (gram)	0.61±0.08	?0.67±0.110	?0.82±0.12	?0.66±0.09	?0.52±0.09	?0.68±0.14	?0.52±0.12
Wet viscosity (gram)	93.4±8.95	?60.169±11.6	?60.2±8.77	?65.4±17.8	?18.4±3.0	?79.1±17.1	?64.1±11.2
								Hot strength (psi)	1921±442	?5242±379	?2043±268	?4316±384	?3351±165	?3725±123	?3905±590
The % elongation	4.2±1.2	?2.9±0.4	?3.8±0.8	?16.9±4.3	?11.1±2.4	?11.4±2.4	?15.0±3.4
								Modulus (psi)	44368±864	?266834±79	?41737±816	?46889±416	?35914±964	?41651±282	?43644±942
Tear resistance (cattle)	0.04±0.01	?0.02±0	?0.05±0.01	?0.09±0.03	?0.12±0.02	?0.05±0.01	?0.08±0.01
								Disintegrate (second)	17.0±4.4	?12±1	?15.3±1.5	?21.9±1.6	?161.0±15.9	?33.2±5.1	?24.1±1.3
Stripping (second)	35.7±2.1	?41±5	?31.0±1.0	?51.6±1.3	＞600	?71.6±3.3	?62.1±2.8

Embodiment 10: the raising of mucosa-adherent

The raising of mucosa-adherent may be used on the film of different-thickness equally.Prepare following preparation: table 10

Composition/test result	Embodiment 1	Embodiment 10a	Embodiment 10b
				The composition of embodiment 1	100％	99.9％	95％
Starch graft copolymer *	0	?0.1％	5％
				Average mucosal adhesive measured value (gram) **	17.5	?26.6	32.3
Standard deviation	7.8	?4.7	4.0
				Mucosal adhesive rate of increase %	Reference value	52％	84.6％

^*Starch graft copolymer is to use 1: 3 Amioca corn starch in water: acrylic acid (providing) by NSCC by polymerization preparation and at United States Patent (USP) 4,690,996 and block and graft copolymerization (the 1st volume, R.J.Ceresa compiles, John Wiley and Sons, 1973) made more detailed description (in this article with two kinds with reference in conjunction with for your guidance) in. ^*Use tensilometer (as Texture Analyzer) to measure mucosa-adherent, it has been measured product of the present invention and has exerted oneself from the separation of simulation mucosal tissue material.Class mucosa material is to use 3.25% gellan gum and 1.6% mucinous mixture to prepare in water.Tested product is introduced and simulated the mucomembranous surface contact 5 seconds and separated.Separating force is to measure by the mucosal adhesive value that is unit with gram force (gram or gram force).The test condition of using is as follows: application rate=3 mm/second, separating rate=2 mm/second ,=150 grams firmly before separating, time of contact=5 second, contact surface=122.7 square millimeter.Embodiment 11: use dried extrusion molding to prepare film

Use mechanical force 77.8 gram polyoxyethylene (Polyox  WSRN-10) to be mixed and following other component of interpolation during mixing: 5.5 gram estradiol, 3.7 gram Herba Menthaes, 3.7 gram propylene glycol, 3.0 restrain aspartames, 2.6 gram citric acids, 3.7 gram Cremphor EL 40 and 0.05 gram benzoic acid.Temperature is maintained at about 70 ℃.

Under 70 ℃, admixture mixed up to evenly.Making it form thickness by extrusion dies then is the film of 5mil.Then this film is cut into dosage form in order to packing.Embodiment 12: the research of the clinical acute irritation of people

Placebo according to embodiment 1 preparation is carried out initial clinical zest research.In 1 hour, 6 kinds of HPMC basement membranes are applied to each among 12 subjects.Before using at every turn, after using at every turn, at last used 1 hour and 24 hours post-evaluation site of administration and mouthful in any acute irritation effect of mucosa.To following indication: erythema, edema, bulla, dipping and discharge are by grade 0-4 marking.Any test position does not detect the zest effect and during using, use the indication that does not detect any zest effect after 1 hour and 24 hours at last at every turn.

Inquire that each subject assesses mouthfeel, product taste, sensation and the dissolution time of at every turn using.All 12 subjects do not experience out any sensation to any using.All subjects describe that film gives them is very level and smooth mouthfeel and points out that the fresh taste of at every turn using film is delivered in the oral cavity.All subjects feel the dissolution time of film very short (＜2 minutes).

Compare with tablet or capsule, most subjects have a preference for film.All subjects represent their preference film rather than solution or syrup.Embodiment 13: pharmacokinetic study shows the bioavailability that has improved medicine with the dosage unit transmission of form membrane

The stripping thin film that is fit to mucosa delivery in the per os and contains active medicine, sildenafil citrate can prepare by table 7.The characteristic of dosage unit is as described in Table 8.

Sildenafil and the commercial tablets (Viagra ) that use in the Sublingual in the contrast mouth under identical dosage are carried out double crossing research.Average plasma levels and pharmacokinetic analysis are shown in Fig. 6 and table 11.Fig. 6 and table 11 show that the bioavailability of stripping film of Isodose is than the bioavailability of tablet high about 25%.The contrast of the pharmacokinetic parameter of table 11:Sildanefil film and Viagra film

Parameter	Sildanefil (S) film	Viagra (S) film	Ratio S/V	The statistics powder
					AUC *(0-t)	?365.5	?293.1	?1.247	?0.86
AUC (infinity)	?378	?3104	?1.218	?0.88
					The C maximum	?109.9	?106.8	?1.029	?0.15
The T maximum	?1	?1	?1	?0.08
					?Ke	?0.354	?0.285	?1.245	?0.32
?T	?1.99	?2.56	?0.775	?0.23

^*Area under a curve

Claims (65)

1. dosage unit comprises: water solublity hydrocolloid, mucomembranous surface form the film of coating, and this film comprises the active medicine of effective dose.

2. according to the dosage unit of claim 1, wherein the aggressive tack value of film is less than 3.5 grams.

3. according to the dosage unit of claim 1, wherein the aggressive tack value of film is less than 2.0 grams.

4. according to the dosage unit of claim 1, wherein the moisture content of film is 0.1%-10%.

5. according to the dosage unit of claim 4, wherein the moisture content of film is less than 5%.

6. according to the dosage unit of claim 1, wherein the wet viscosity value of film is greater than 35 grams.

7. according to the dosage unit of claim 2, wherein the wet viscosity value of film is greater than 35 grams.

8. according to the dosage unit of claim 1, wherein for 2% polymer solution, the gelation temperature of hydrocolloid is higher than 70 ℃.

9. according to the dosage unit of claim 1, wherein the hydration rate of hydrocolloid had been 5-20% in 24 hours under 75% humidity and the room temperature.

10. according to the dosage unit of claim 1, wherein hydrocolloid exists with the concentration range of 5%-99%.

11. according to the dosage unit of claim 1, wherein hydrocolloid is a kind of polymer that comprises natural, half-natural and synthetic biopolymer that is selected from.

12. according to the dosage unit of claim 11, wherein hydrocolloid is selected from polysaccharide and polypeptide.

13. according to the dosage unit of claim 11, wherein hydrocolloid is a hydroxypropyl methyl cellulose polymers.

14. according to the dosage unit of claim 11, wherein the molecular weight of hydroxypropyl methyl cellulose polymers is less than 200,000.

15. according to the dosage unit of claim 1, wherein film also comprises one or more emulsifying agents, plasticizer, flavor improving agent, water solublity inert filler, antiseptic, coloring agent and stabilizing agent in addition.

16. according to the dosage unit of claim 15, wherein the concentration range of emulsifying agent is 0.1-10% (weight).

17. the dosage unit according to claim 15 is a dosage unit, wherein flavor improving agent is made up of one or more sweeting agents, correctives and taste screening agent.

18. according to the dosage unit of claim 15, wherein the concentration range of the water solublity inert filler that contains of film is 0.5 to 50%.

19. according to the dosage unit of claim 15, wherein the concentration range of antiseptic is 0.01 to 10%.

20. according to the dosage unit of claim 1, wherein active medicine exists with 0.01 to 75% concentration range.

21. according to the dosage unit of claim 1, wherein active medicine is selected from therapeutic agent, nutritional supplement and health-care agent.

22. according to the dosage unit of claim 21, wherein therapeutic agent is sildenafil citrate.

23. according to the dosage unit of claim 21, wherein therapeutic agent is selected from nicotine, hydromorphone, oxibutynin and estradiol.

24. according to the dosage unit of claim 1, wherein the dry film thickness range of film is 1-20mil.

25. according to the dosage unit of claim 24, wherein the build of film is less than 10mil.

26. according to the dosage unit of claim 1, wherein the hot strength of film is greater than 1500psi.

27. according to the dosage unit of claim 1, wherein the percentage elongation of film is less than 20%.

28. according to the dosage unit of claim 1, wherein film is in 1-300 disintegrate in second.

29. according to the dosage unit of claim 1, wherein the modulus ranges of film is 35,000-300,000psi.

30. according to the dosage unit of claim 1, wherein the dissolution time scope of film is 10-600 second.

31. according to the dosage unit of claim 1, wherein the hot strength of film is greater than 1500psi, the percentage elongation of film is less than 20%, and the disintegration time scope is that 1-300 second and dissolution time scope are 10-600 second.

32. according to the dosage unit of claim 1, wherein film has the effective wetting curve under the situation of the mixture that lacks two kinds of non-ionic surface medicines.

33. according to the dosage unit of claim 1, wherein active medicine is encapsulated within the polymer, wherein the chemical of polymer or physical property are different from hydrocolloid, and entrapped medicine is dispersed in the film.

34. according to the dosage unit of claim 1, wherein dosage unit comprises more than one active medicine.

35. according to the dosage unit of claim 1, wherein dosage unit also comprises mucosal adhesive promoter in addition, mucosal adhesive promoter is positioned at film.

36. according to the dosage unit of claim 35, wherein mucosal adhesive promoter is starch graft copolymer.

37. according to the dosage unit of claim 35, wherein mucosal adhesive promoter exists with 0%-50% (weight).

38. the preparation method of the dosage unit of a suitable mucosa delivery comprises:

(a) thus hydrocolloid dissolved in a certain solvent form a kind of basic preparation uniformly;

(b) add active medicine and at least a reagent that is selected from emulsifying agent, plasticizer, flavor improving agent, water solublity inert filler, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent in the hydrocolloid preparation a kind of the coating or squeezable mixture of formation;

(c) form a kind of mucomembranous surface by mixture and form the film of coating for being packaged into dosage unit.

39. according to the method for claim 38, wherein step (b) also comprises in addition described mixture is applied on the counterdie.

40. the preparation method of the dosage unit of a suitable mucosa delivery comprises:

(a) by any order mixing water colloid, active medicine and at least a reagent that is selected from emulsifying agent, plasticizer, flavor improving agent, water solublity inert filler, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent in the container of being furnished with thermal source and mechanical mixing equipment;

(b) during adding various compositions to container and afterwards blending constituent is mixed and with effective dose heat fusing major part mixture;

(c) make mixture form film.

41. according to the method for claim 40, wherein step (b) also comprises described mixture coating in addition or is expressed on the counterdie.

42. according to the method for claim 40, wherein step (c) comprises also that in addition removing flexible membrane and cross cutting film from counterdie forms the stripping dosage unit.

43. one kind gives subject's method with medicine, comprising:

(a) a kind of water solublity hydrocolloid of acquisition, mucomembranous surface form the film of coating, and this film comprises the active medicine of effective dose;

(b) this film is placed on subject's mucomembranous surface so that discharge active medicine.

44. according to the method for claim 43, wherein the aggressive tack value of film is less than 3.5 grams.

45. according to the method for claim 43, wherein the moisture content of film is 0.1%-10%.

46. according to the method for claim 43, wherein the hydration rate that has of hydrocolloid had been 5-20% in 24 hours under 75% humidity and the room temperature.

47. according to the method for claim 43, wherein hydrocolloid exists with the concentration range of 5%-99%.

48. according to the method for claim 43, wherein hydrocolloid is a hydroxypropyl methyl cellulose polymers.

49. according to the method for claim 48, wherein the molecular weight of hydroxypropyl methyl cellulose polymers is less than 200,000.

50. according to the method for claim 43, wherein the hydrocolloid mixture also comprises one or more emulsifying agents, plasticizer, flavor improving agent, water solublity inert filler, antiseptic, coloring agent and stabilizing agent in addition.

51. according to the method for claim 43, wherein active medicine exists with the concentration range of 0.01-75%.

52. according to the method for claim 43, wherein active medicine is selected from therapeutic agent, nutritional supplement and health-care agent.

53. according to the method for claim 52, wherein therapeutic agent is sildenafil citrate.

54. according to the method for claim 52, wherein therapeutic agent is selected from nicotine, hydromorphone, oxibutynin and estradiol.

55. according to the method for claim 43, wherein dry film thickness range is 1-20mil.

56. a dosage unit comprises: with film that mucomembranous surface contacts in the water solublity hydrocolloid and the sildenafil citrate of effective dose.

57. according to the dosage unit of claim 56, wherein sildenafil citrate and xylitol form solid dispersion.

58. a method for the treatment of erection disturbance comprises:

(a) obtain a kind of in the water solublity hydrocolloid the sildenafil that comprises effective dose and the film of the solid dispersion of xylitol;

(b) film is administered to the oral mucosa surface.

59. according to the method for claim 58, wherein film on the oral mucosa surface in 10-600 basic stripping fully in second.

60. according to the method for claim 59, wherein film basic stripping fully in 200 seconds.

61. the preparation method of the dosage unit of the mucosal of a suitable treatment erection disturbance comprises:

(a) by the solid dispersion and at least a reagent that is selected from emulsifying agent, plasticizer, flavor improving agent, coloring agent, antiseptic, penetration enhancer, stabilizing agent and buffer agent of any order mixing water colloid, sildenafil and xylitol in the container of being furnished with thermal source and mechanical mixing equipment;

(b) during adding various compositions to container and afterwards blending constituent is mixed and with effective dose heat fusing major part mixture;

(c) make mixture form film.

62. according to the method for claim 61, wherein sildenafil is 9/1 to the ratio of xylitol.

63. according to the method for claim 61, wherein the water solublity of sildenafil is at least 20 mg/ml.

64. according to the method for claim 63, wherein the water solublity of sildenafil is about 50 mg/ml.

65. a dosage unit comprises: the sildenafil citrate of effective dose; Sildenafilcitrate forms in the solid dispersion with water solublity inert filler, thereby solid dispersion mixes the formation film with the film former that comprises α-hydropolymer, thereby described film can discharge sildenafil citrate in the mucomembranous surface stripping.

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